The multidrug resistance-associated protein (MRP) subfamily of the ATP-binding cassette (ABC) transporters plays a key role in protecting cells from drugs and environmental toxins such as heavy metals (mercury, arsenic, lead, and cadmium). The MRPs (also called ABCCs) are distinguished from other ABC transporters by two striking hallmarks: 1) they contain an additional "N-terminal extension" with a conserved region called L0, and 2) they transport substrates in the form of glutathione (GSH)-conjugates or complexes. Here, we will use the powerful genetic, molecular, and cellular tools available in Saccharomyces cerevisiae to address several key issues of the MRPs. Our specific aims are to: 1) determine whether conserved residues within the L0 of MRPs are specific for GSH binding; 2) assess whether novel interactors, recently identified for the yeast MRP Ycflp, play an integral role in the general mechanism of MRP transport; and 3) test the possibility that a major role of the MRP's is to dispose of potentially harmful "metabolic detritus", using genetic and chemical screens. Overall, our analysis may suggest more effective therapies for MRP- based diseases (e.g. DJS, PXE, cystic fibrosis) and/or aid in reducing damage from environmental toxins.